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@ARTICLE{Jrgens:126795,
      author       = {K. Jörgens and S. J. Stoll and J. Pohl and T. H. Fleming
                      and C. Sticht and P. P. Nawroth and H.-P. Hammes and J.
                      Kroll$^*$},
      title        = {{H}igh tissue glucose alters intersomitic blood vessels in
                      zebrafish via methylglyoxal targeting the {VEGF} receptor
                      signaling cascade.},
      journal      = {Diabetes},
      volume       = {64},
      number       = {1},
      issn         = {1939-327X},
      address      = {Alexandria, Va},
      publisher    = {Assoc.},
      reportid     = {DKFZ-2017-02823},
      pages        = {213 - 225},
      year         = {2015},
      abstract     = {Hyperglycemia causes micro- and macrovascular complications
                      in diabetic patients. Elevated glucose concentrations lead
                      to increased formation of the highly reactive dicarbonyl
                      methylglyoxal (MG), yet the early consequences of MG for
                      development of vascular complications in vivo are poorly
                      understood. In this study, zebrafish were used as a model
                      organism to analyze early vascular effects and mechanisms of
                      MG in vivo. High tissue glucose increased MG concentrations
                      in tg(fli:EGFP) zebrafish embryos and rapidly induced
                      several additional malformed and uncoordinated blood vessel
                      structures that originated out of existing intersomitic
                      blood vessels (ISVs). However, larger blood vessels,
                      including the dorsal aorta and common cardinal vein, were
                      not affected. Expression silencing of MG-degrading enzyme
                      glyoxalase (glo) 1 elevated MG concentrations and induced a
                      similar vascular hyperbranching phenotype in zebrafish. MG
                      enhanced phosphorylation of vascular endothelial growth
                      factor (VEGF) receptor 2 and its downstream target
                      Akt/protein kinase B (PKB). Pharmacological inhibitors for
                      VEGF receptor 2 and Akt/PKB as well as MG scavenger
                      aminoguanidine and glo1 activation prevented MG-induced
                      hyperbranching of ISVs. Taken together, MG acts on smaller
                      blood vessels in zebrafish via the VEGF receptor signaling
                      cascade, thereby describing a new mechanism that can explain
                      vascular complications under hyperglycemia and elevated MG
                      concentrations.},
      keywords     = {VEGF protein, zebrafish (NLM Chemicals) / Vascular
                      Endothelial Growth Factor A (NLM Chemicals) / Zebrafish
                      Proteins (NLM Chemicals) / enhanced green fluorescent
                      protein (NLM Chemicals) / Green Fluorescent Proteins (NLM
                      Chemicals) / Pyruvaldehyde (NLM Chemicals) / Vascular
                      Endothelial Growth Factor Receptor-2 (NLM Chemicals) / kdr
                      protein, zebrafish (NLM Chemicals) / Proto-Oncogene Proteins
                      c-akt (NLM Chemicals) / Glucose (NLM Chemicals)},
      cin          = {A190},
      ddc          = {610},
      cid          = {I:(DE-He78)A190-20160331},
      pnm          = {321 - Basic Concepts (POF3-321)},
      pid          = {G:(DE-HGF)POF3-321},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:25092676},
      doi          = {10.2337/db14-0352},
      url          = {https://inrepo02.dkfz.de/record/126795},
}